Seltorexant as Adjunctive Therapy for MDD With Insomnia

Jane Tiller, MD, discussed phase 3 clinical trial data on seltorexant, a selective orexin-2 receptor antagonist under development as adjunctive therapy for major depressive disorder (MDD) with residual insomnia symptoms.

Tiller framed MDD as a major global public health problem, noting approximately 22 million people in the United States are affected, and emphasizing that even with currently approved treatments, approximately two-thirds of patients experience residual symptoms rather than full remission. She positioned seltorexant as targeting this unmet need, particularly for patients with partial response to initial antidepressant therapy and persistent insomnia. Mechanistically, Tiller explained that orexin-2 receptor antagonism is believed to normalize the hyperarousal characteristic of MDD and promote restorative sleep, thereby interrupting the bidirectional cycle linking poor sleep and depressed mood.

Tiller presented data from a placebo-controlled trial in which adjunctive seltorexant, added to an SSRI or SNRI, achieved statistically significant improvement on all primary and key secondary endpoints, including the Montgomery–Asberg Depression Rating Scale with sleep items removed—demonstrating an antidepressant effect independent of simple sedation—as well as on patient-reported sleep disturbance.¹

She also shared results from MDD3005, a 26-week, head-to-head phase 3 trial comparing adjunctive seltorexant with adjunctive quetiapine extended-release, a commonly used augmentation strategy.² Both agents produced statistically similar, clinically meaningful improvement in depressive symptoms. However, seltorexant demonstrated a more favorable metabolic and tolerability profile, with significantly less weight gain, a 4-fold lower rate of somnolence, and fewer treatment-related study withdrawals compared with quetiapine extended-release. Tiller also noted a trend toward metabolic improvement with seltorexant among patients with baseline metabolic risk factors, contrasted with a trend toward worsening with quetiapine. She concluded that the data demonstrate comparable efficacy with a differentiated, more favorable side-effect profile, supporting individualized, shared decision-making between physicians and patients regarding adjunctive treatment selection.

Dr Tiller is global head of clinical development for neuroscience at Johnson & Johnson.

References

1. Johnson & Johnson's investigational seltorexant shows numerically higher response in patients with depression with insomnia symptoms, with fewer side effects compared to quetiapine XR. Press release. September 22, 2025. Accessed June 24, 2026. https://www.jnj.com/media-center/press-releases/johnson-johnsons-investigational-seltorexant-shows-numerically-higher-response-in-patients-with-depression-with-insomnia-symptoms-with-fewer-side-effects-compared-to-quetiapine-xr

2. Pinter C, Thase ME, McIntyre RS, et al. Safety, tolerability, and preliminary efficacy of seltorexant versus quetiapine extended release as adjunctive therapy in major depressive disorder: a randomized, flexible-dose, 6-month, parallel-group, exploratory study. Int J Neuropsychopharmacol. 2026;29(4):pyag009.